Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes
Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassaï B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C.
BMJ. 2011 Jul 26;343:d4169. doi: 10.1136/bmj.d4169. Review.
Objective To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes.
Meta-analysis of randomised controlled trials.
Medline, Embase, and the Cochrane database of systematic reviews.
Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥18 years) with type 2 diabetes.
Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events.
Synthesis of results
Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with χ², τ², and I2 statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score.
13 studies were included. Of 34 533 patients, 18 315 received intensive glucose lowering treatment and 16 218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001).
The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomized controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes.
Globally, the number of adults with diabetes was estimated at 150 million in 2000, a figure that is expected to increase to 366 million by 2030.1 Epidemiological evidence indicates that type 2 diabetes is an independent risk factor for cardiovascular disease and microvascular complications, such as retinopathy. The rate of cardiovascular disease is about twice as high in people with diabetes than without.2,3 Intensive glycaemic control has been suggested as an effective treatment to reduce the burden of cardiovascular disease and microvascular complications in people with diabetes.4 Current guidelines recommend a target glycated haemoglobin level (HbA1c) of 7% or less.5 The results of major randomised clinical trials on the benefits of such treatment are, however, controversial.6-8 Several meta-analyses evaluating the effect of intensive glucose lowering in people with diabetes are currently available.9-11 However, these published meta-analyses focused mainly on the effect of treatment on macrovascular events, such as myocardial infarction. This updated meta-analysis was carried out taking into consideration both microvascular complications and cardiovascular events as well as severe hypoglycaemia related to intensive glycaemic control and the level of evidence of the selected studies.
Overall, 13 randomised controlled trials fulfilled the inclusion criteria and were included in the meta-analysis6-9, 13-21 Baseline characteristics of the selected studies are summarized in table 1. The analysis was based on 34 533 patients (60% men), with a mean age of 62 (range 49-66) years, a baseline mean HbA1c level of 7.9% (range 7.1-9.5%), and a mean body mass index of 31 (range 20-32). The mean duration of diabetes was 7.8 (range 0-12) years. Overall, 39% of patients already had a cardiovascular event at baseline. In total, 18 315 were randomised to the intensive treatment group and 16 218 to the standard treatment group. The mean duration of follow-up was 5.0 (range 1-10) years.
Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or death from cardiovascular causes (1.11, 0.86 to 1.43; fig 1). Heterogeneity between trials was significant for all cause mortality (P=0.09, τ2=0.01, I2=42%) and for cardiovascular deaths (P=0.006, τ2=0.04, I2=61%). After exclusion of trials with a Jadad score of 3 or less (see web extra), the estimated odds ratio for all cause mortality did not change (1.06, 0.84 to 1.34), whereas the rate of cardiovascular deaths tended to be higher, although not significantly, in the intensive treatment group (1.58, 0.60 to 4.17). Heterogeneity among high quality trials was persistent for the rate of cardiovascular deaths (I2=70%). This heterogeneity could not be explained.
In the intensive treatment group the rate of non-fatal myocardial infarctions was significantly reduced (0.85, 0.74 to 0.96; P<0.001) and there was a non-significant trend towards a reduction of all myocardial infarctions (0.90, 0.81 to 1.01; P=0.02). No heterogeneity existed between trials for these end points (I2=0%). Intensive treatment was not associated with a reduction in the risk of non-fatal strokes (1.00, 0.83 to 1.21), all strokes (0.96, 0.83 to 1.13), or congestive heart failure (1.17, 0.91 to 1.50). Heterogeneity was evident among studies for congestive heart failure (P=0.01, τ2=0.04, I2=59%), but not for the two other end points. Intensive treatment was associated with a significant reduction in the rate of microalbuminuria (0.90, 0.85 to 0.96). Compared with the standard treatment group, the risk of severe hypoglycaemia was more than twice as high in the intensivetreatment group (2.33, 1.62 to 3.36). Heterogeneity was evident among studies (P=0.03, τ2=0.05, I2=63%).